This PPT is part of a lecture given to second year pharmacy students in a pharmacology & toxicology class.

1. Mood Stabilizers: Agents for
Bipolar Disorder
Brian J. Piper, Ph.D., M.S.
January 29, 2013

2. Objectives
• Bipolar I versus II
• Lithium
– Adverse effects
• Anti-psychotics

3. Bipolar Disorder: General
• Afflicts 1% of the population
• About 30% will develop symptoms before age
20
• High heritability but limited understanding of
pathophysiology
Stahl (2008). Essential Psychopharmacology, p. 711.

4. DIGFAST – Mental Status Exam
• Distractible
• Increased activity/psychomotor agitation
• Grandiosity/Super-hero mentality
• Flight of ideas or racing thoughts
• Activities that are dangerous or hypersexual
• Sleep decreased
• Talkative or pressured speech
Nancy Rappaport, MD

6. ------
---------------
Stahl, S. (2008). Essential Psychopharmacology (3rd ed), p. 457.

7. ------- -------
Stahl, S. (2008). Essential Psychopharmacology (3rd ed), p. 459.

8. Diagnosis of Bipolar
• Bipolar I: • Bipolar II:
– manic episode – hypomanic episode
– depression not – major depressive episode
required – not due to schizophrenia or
– not due to recreational drugs
schizophrenia or
recreational drugs

9. Current Mood Stabilizers: Or
Stahl, S. (2008). Essential Psychopharmacology, p. 669.

10. Treatment of Bipolar Disorder
Mood stabilizers* Anticonvulsants Second
generation
Lithium Carbamazepine
antipsychotics
Valproate Lamotrigine
Clozapine
Olanzapine Topiramate
Risperidone
* FDA approved
Gabapentin
Quetiapine
Nonpharmacologic Somatic therapies Ziprasidone
therapies
ECT
CBT
Light therapy
Other psychotherapies Aripiprazole
TMS; VNS (?)
Iloperidone
2/15/2013

11. History of Lithium
• Lithium carbonate (Li2CO3) 1912 - 1980
• John Cade, Australian psychiatrist, on giving
lithium to guinea pigs:
– “After a latent period of about two-hours, the animals, although fully conscious
became extremely lethargic and unresponsive to stimuli for one to two hours before
once again becoming timid and active. Those who have experimented with guinea
pigs know to what extent a ready startle reaction is part of their makeup. It was even
more startling to find that after the injection of a solution of lithium carbonate they
could be turned on their backs and that, instead of the usual frantic righting
behavior, they merely lay there and gazed placidly back at him.”

12. Cade’s Case Series (X)
• Case I- “W.B., a male, 51, who had been in a state of chronic manic excitement for 5
years, restless, dirty, destructive, mischievous and interfering, had long been regarded as the
most troublesome patient in the ward. From the start of treatment (March 29, 1948) … he
steadily settled down and in three weeks was enjoying the unaccustomed surroundings of
the convalescent ward (previously confined to chronic ward). He was kept under observation
for 2 months. He remained perfectly well and left the hospital on July 19, 1948”.
• Case VIII-”W.M., a man of 50, was suffering from an attack of recurrent mania, the first of
which he had at the age of 20. The present attack had lasted two months and showed no
signs of abating. He was garrulous, euphoric, restless and unkempt when he started taking
lithium (Feb 11, 1949). Two days later he was reported to be quieter… By the end of two
weeks he was practically normal-quiet, tidy, rational, with insight into his previous
condition.”
• Case IX- “W.S., a powerfully built man of 47 had suffered from recurrent manic phases since
age 25. … On Feb 11, 1949, he commenced taking lithium … He was considerably quieter 2
days later, was working happily in the kitchen … and by the 9th day was practically normal. …
An acquaintance who has known the patient for years reports that he has never seen him as
normal as at present”.
Cade, J. F. J. (1949). Medical Journal of Australia, 2(10), 349-351.

13. Individual Symptom Control with Lithium
ECT
↑ECT
Li
Plac
Schou et al. (1954). J Neurol Neurosurg Psychiatry, 17, 250-260.

14. History of Lithium in U.S.
• 1940-1960s: lithium chloride used as a
substitute for sodium chloride, poisonings
• 1970: FDA approval, gradual increase as
monotherapy
• 2000s – increased use in combos
– Evidence Based Medicine: based on RCTs
– Eminence Based Medicine: based on clinical
experience & expert opinion

15. Adverse Effects of Lithium
• polydipsia/polyuria (70%)
• hand tremor (40%)
• other neuro (40%)
– headache
– concentration/↓memory
• kidney: risk of diabetes insipidus & nephrotoxicity
• thyroid: hypothyroidism/goiter (20%)
Drayton (2011). In DiPiro Pharmacotherapy: A Pathophysiologic Approach.

16. MOA of Lithium
• Diverse effects but therapeutic mechanism
unknown
• Candidates
– Increase 5-HT release
– Inhibits 2nd messenger systems
Effect of lithium on the IP3 (inositol trisphosphate)
and DAG (diacylglycerol) second messenger
system.
Lithium, by inhibiting the recycling of inosital
substrates, may cause the depletion of PIP2
(phosphatidylinositol-4,5-bisphosphate)
and therefore reduce release of IP3 & DAG.
Meltzer, H. (2011). In Lange’s Basic & Clinical Pharmacology, p. 515.

17. Lithium During Pregnancy
• Category D: There is positive evidence of human fetal risk
based on adverse reaction data from investigational or marketing
experience or studies in humans, but potential benefits may
warrant use of the drug in pregnant women despite potential risks.
• Better profile than anti-psychotics or anti-convulsants
• Complex risk to benefit ratio
• Breast feeding is discouraged
Fig from: Sykes et al. (1976). British Medical Journal, 1299.

18. • The reason for their efficacy
in treating bipolar is unknown
but could involve other
targets besides blocking D2/5-
HT2A
• Acute mania: haloperidol
• Depression in bipolar:
quetiapine
Stahl, S. (2008). Essential Psychopharmacology, p. 692.

19. Anti-Convulsants & Bipolar
• Example: valproic acid
• MOA: voltage sensitive channels (Na, Ca)
• Adverse effects: weight gain, hair
loss, sedation

20. Summary
• Lithium remains a first choice for BP I despite
a narrow therapeutic index
• Drug combinations (Li + anti-psychotics + anti-
convulsants), despite limited clinical
research, are increasingly common

21. More to explore

22. National trends in visits with a diagnosis of bipolar disorder as a percentage of total office-based
visits by youth (aged 0-19 years) and adults (aged >= 20 years)
Moreno, C. et al. (2007). Arch Gen Psychiatry, 64, 1032-1039.
Trish Example (1st min): http://www.youtube.com/watch?v=rcl09ztmoDw

23. Reduced Lifespan
(N = 5,036,662)
Male Male Female Female
Life Expectancy Years Life Years Lost
Lost Expectancy
All (Psychiatric 76.5 NA 80.9 NA
History - )
Schizophrenia 57.8 18.7 64.6 16.3
Bipolar 62.9 13.6 68.8 12.1
BP Contributing Factors:
self-care (circulatory), accident,
homicides, suicide
adverse effects?
Laursen (2011). Schizophrenia Research, 131, 101-104.